Novel chiral ethers and their use in resolution of alcohols and phenols

ABSTRACT

Novel ethers of organic compounds containing chiral atoms of the formula ##STR1## wherein A is a hydrocarbonated chain of 1 to 10 groups, the said chain containing one or more heteroatoms, one or more unsaturations, the assembly of the groups constituting the chain may represent a mono- or polycyclic system, including a system of the spiro or endo type, the chain A can contain one or more chiral atoms or the lactone moiety can present a chirality due to the dissymetric spatial configuration of the whole of the molecule and Z is selected from the group consisting of primary, secondary or tertiary alcohol moiety containing at least an asymetric carbon atom, a phenol moiety substituted comprising at least one asymetric carbon atom and an substituted alcohol or phenol moiety with a chirality due to the dissymetric spatial configuration of the whole of the molecule, with the proviso Z is not (R) or (S) α-cyano-3-phenoxy-benzyl when A is ##STR2## which are useful for the resolution of compounds of the formulae ##STR3## wherein A and Z have the above definitions and X is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms.

STATE OF THE ART

The most closely related art is believed to be U.S. Pat. Nos. 3,723,469and 4,014,918.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel products offormula I and to provide a novel process for their preparation.

It is another object of the invention to provide a novel process for theresolution of compounds of formulae II or III.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel ethers of the invention having an organic group comprisingchiral atoms are comrised of compounds of the formula ##STR4## wherein Ais a hydrocarbonated chain of 1 to 10 groups, the said chain containingone or more heteroatoms, one or more unsaturations, the whole of thegroups constituting the chain may represent a mono- or polycyclic systemincluding a system of the spiro or endo type, the chain A can containone or more chiral atoms or the lactone moiety can present a chiralitydue to the dissymetric spatial configuration of the whole of themolecule and Z is selected from the group consisting of primary,secondary or tertiary alcohol moiety containing at least one asymetriccarbon atom, a phenol moiety substituted comprising at least oneasymetric carbon atom and an substituted alcohol or phenol moiety with achirality due to the dissymetric spatial configuration of the whole ofthe molecule, with the proviso Z is not (R) or (S)α-cyano-3-phenoxy-benzyl when A is ##STR5##

Among the compounds of formula I are those wherein the A chain containsone or more asymetric carbon atoms and the chemical structure imposes bythe hydroxyl an unequivocally spatial disposition. In this type ofcompound, the two different atoms or radicals which are substituted onthe carbon atoms of the chain are selected from at least one member ofthe groups consisting of (a) hydrogen, halogen, nitro, alkyl of 1 to 10carbon atoms, cycloalkyl of 3 to 6 carbon atoms and phenyl optionallysubstituted with at least carbon atoms and phenyl optionally substitutedwith at least one member of the group consisting of halogen, alkyl,alkoxy and alkylthio of 1 to 6 carbon atoms, carboxyl, --CN, --CHO,##STR6## and acyl of an organic carboxylic acid of 1 to 10 carbon atoms,(b) --NH--R₁ wherein R₁ is selected from the group consisting ofhydrogen, alkyl of 1 to 6 carbon atoms, benzoyl, ##STR7## wherein AlK ofalkyl of 1 to 6 carbon atoms and (c) ##STR8## wherein R₂ and R₃ areindividually alkyl of 1 to 6 carbon atoms, or R₂ is carboxyl and R₃ isbenzyl or R₂ and R₃ together with the nitrogen atom to which they areattached form a 6-member heterocycle.

Among the particularly interesting families of compounds of formula Iare those wherein A is an aliphatic hydrocarbon chain of 2 to 3 carbonatoms, those wherein A is an aliphatic hydrocarbon chain interruptedwith a heteroatom, those wherein A is an aliphatic hydrocarbon chaincontaining a double bond, those wherein A is monocyclic hydrocarbonchain of 3 to 6 carbon atoms optionally containing one unsaturation; andthose wherein A is a bicyclic hydrocarbon chain of 5 to 10 carbon atomsoptionally containing one unsaturation.

Particularly preferred compounds of formula I are those wherein A hasthe formula ##STR9## those wherein A has the formula ##STR10## and Y andY' are individually selected from the group consisting of hydrogen,chlorine, fluorine, bromine and alkyl of 2 to 6 carbon atoms or Y and Y'together with the carbon to which they are attached form a carbonhomocycle of 3 to 7 carbon atoms, those wherein A has the formula##STR11## and R is selected from the group consisting of --O--, --S--,--NH-- and --NR'-- and R' is alkyl of 1 to 6 carbon atoms, those whereinZ has the formula ##STR12## those wherein Z has the formula ##STR13##and R" is selected from the group consisting of alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atomsand --CN.

In the compounds of formula I, the group Z is derived from an alcoholwhich may be aliphatic, cycloaliphatic or aromatic, mono or polycyclic,primary, secondary or tertiary alcohol. Among the preferred alcohols arethe cyanohydrins. Z may equally be derived from a phenol substitutedwith one or more substituents containing at least one asymetric carbonatom.

Among the specific preferred compounds or mixtures of compounds offormula I are a mixture of (1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1R,5S)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxobicyclo-(3,1,0)-hexan-2-one,a mixture of (1S,5R)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1S,5R)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,(1R,5S)6,6-dimethyl-4(R)-[1-(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,(1S,5R)6,6-dimethyl-4(R)-[1-(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,(1R,5S)6,6-dimethyl-4(R)-[3',3'-dimethyl-butyrolacetone-2'(S)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,(1R,5S)6,6-dimethyl-4(R)-(3',3'-dimethyl-butyrolactone-2'(R)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,mixtures of the said butyrolactones, (3R, 3aR, 4S, 7R, 7aS) 3-[(1'R),(2'S), (5'S), (5'R) 2'-isopropyl-5'-methylcyclohexanoxy]-tetrahydro-4,7-methanoisobenzofuran-1-one, (3R, 3aR, 4S,7R, 7aS) 3-[(1'S), (2'R), (5'S)2'-isopropyl-5'-methyl-cyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one,mixtures of the last two compounds, (1R,5S) 6,6-dimethyl-4(R)-[(1'R),(2' S), (5'R)2'-isopropyl-5'-methyl-cyclohexanoxy]-3-oxabicyclo-3,1,0)-hexan-2-one,(1R,5S) 6,6-dimethyl-4(R)-[(1'S), (2'R), (5'S)2'-isopropyl-5'-methyl-cyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand mixtures of the last two compounds.

The novel process of the invention for the preparation of compounds offormula I comprises reacting a lactonic compound of the formula##STR14## wherein A has the above definition and X is selected from thegroup consisting of hydrogen and alkyl of 1 to 4 carbon atoms in thepresence of an acid with a substituted phenol or alcohol of the formula

    Z--OH                                                      III

wherein Z has the above definition to obtain either a compound of theformula ##STR15## wherein the chiral atoms possess a well definedconfiguration when the lactone and the alcohol or phenol possess one ormore chiral atoms of well defined configuration, or a mixture ofdiasteroisomers named I_(B) when the lactone is a well defined opticalisomer and the chiral centers of the alcohol or phenol do not have anunequivocal configuration, or a mixture of diastereoisomers named I_(C)when the alcohol or phenol is a well defined optical isomer and thechiral atoms of the lactone do not have an unequivocal configuration andthen separating by physical methods the diastereoisomeric etherscontained either in the mixtures of type I_(B) or mixtures of type I_(C)and notably the ethers of formula I_(A) whose chiral centers are of anunquivocal configuration.

The acid agent in whose presence the reaction of the phenol or alcoholwith the lactone is effected may be selected from the group consistingof sulfonic acids, perchloric acid and 5-sulfosalicyclic acid. The waterof reaction or the alcohol formed is preferably removed by azeotropicdistillation at reflux in an organic solvent such as chlorinatedsolvents, aromatic or aliphatic hydrocarbons or ethers, but the reactionmay be effected in the absence of a solvent under reduced pressure. Thephysical separation of the diastereoisomeric ethers is preferablyeffected by crystallization or chromatography. If the one or more chiralatoms of the lactonic copule II are each of (R) or (S) determined stericconfiguration, when one or more of asymetric carbon atoms of thesubstituded alcohol or phenol III are also individually of (R) or (S)determined steric configuration, there is directly obtained withretention of configuration the compounds of formula I corresponding tothose of formula I_(A). When in the process, the substituted alcohol orphenol III possesses one or more non-resolved asymetric carbon atoms,there is obtained a mixture of diastereoisomeric ethers I denominated asformula I_(B) which may then be separated by a physical treatment suchas chromatography or crystallization from a solvent. The latter case isparticularly interesting.

After separation of the formed diastereoisomeric ethers of formulaI_(B), for example after separation of a compound of formula I_(A), asimple hydrolysis or alcoholysis such as indicated above, permits theobtention of resolved substituted alcohols or phenols on a level of fromthe initial racemic asymetric carbon atoms. When the substituted alcoholor phenol possesses M non-resolved chiral centers, there are formed 2 Mdiastereoisomers similar to I_(A) which convenient can be separated intoindividual of formula I_(A). One may recover by another way the lactoniccompound of formula II where the chiral atoms are of (R) or (S)determined steric configuration which exist starting from the compoundsof formmula II.

In an analogous fashion in the process of the preparation of thecompounds of formula I, if one or more asymetric carbon atoms of thesubstituted alcohols or phenols of formula III are (R) and (S)determined steric configurations, when one or more chiral atoms of thelactonic copule are also (R) or (S) determined steric configuration, oneobtains directly with retention of the configuration the correspondingcompounds indicated as I_(A).

When in the process, the lactonic couple has the (R,S) racemicconfiguration due to one or more unresolved chiral centers, there isobtained a mixture of diastereoisomeric ethers of formula I designatedas I_(C) which may be separated by physical means, especiallychromatography or crystallization from a solvent, with the latter beingparticularly interesting.

After separation of the formed diastereoisomeric ethers I_(C), forexample after separation of I_(A), a simple hydrolysis or alcoholysis asindicated above permits the obtaining of resolved lactonic compound onthe level of the chiral atoms of (R,S) racemic configuration in theinitial mixture. When the lactonic couple possess n unresolved chiralcenters, there are formed 2 n diastereoisomers looking like I_(A) whicheventually can be separated into individual like I_(A).

Another way, the utilized substituted alcohol or phenol III is recoveredof which the asymetric carbon atoms have the (R) or (S) determinedsteric configuration as in the starting compound ZOH.

In all of the preceding discussion, the presence of one or more resolvedor non-resolved chiral centers in compounds II or III imply thefollowing different possibilities: either none of the chiral centerspossesses an unequivocal (R) or (S) configuration and the molecule isthen a mixture of racemic groups of enantiomers or one part of thechiral centers possesses an unequivocal (R) or (S) configuration and themolecule is then a mixture of diastereoisomers or all the chiral centershave an unequivocal (R) or (S) configuration and then the molecule isconsidered to be a well defined optical isomer.

Besides the asymetry due to the presence of chiral centers in themolecule of compounds II or III, they can have a geometric isomerism dueto the presence of one or more (E) or (Z) double bonds so that asupplemental chirality due to the spatial conformation of the ensemblyof the molecule of which the atoms constituting it is able, for example,to divide into 2 orthogonal planes. The process of the invention equallyapplies in this case and one is still able to effect a resolution of oneor more racemic asymetrical carbon atoms presented in a copule of etherI thanks to the chirality of the other part of ether I.

The invention has as its subject, preferably, a process for thepreparation of compounds of formula I comprising in that compound II isthe lactone of a racemate or an optical isomer of cis2,2-dimethyl-3-(dihydroxymethyl)-cyclopropane-1-carboxylic acid andcompound III is an optical isomer or racemate of1-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-en-4-one and theresulting diastereoisomeric compound I is separated by crystallizationfrom an organic solvent. Another preferred process of the inventioncomprises reacting the lactone of a racemate or optical isomer of cis2,2-dimethyl-3-(dihydroxymethyl)-cyclopropane-1-carboxylic acid and aracemate or optical isomer of 2-hydroxy-3,3-dimethyl-butyrolactone orpantolactone and the resulting diastereoisomeric compound I is separatedby chromatography.

Another process of the invention comprises reacting a racemate oroptical isomer of 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-onewith a racemate or optical isomer of menthol and the resultingdiastereoisomeric compound I is separated by chromatography. A furtherprocess of the invention comprises reacting the lactone of a racemate oran optical isomer of cis2,2-dimethyl-3-(dihydroxymethyl)-cyclopropane-1-carboxylic acid and aracemate or optical isomer of menthol and the resultingdiastereoisomeric compound is separated by chromatography.

The process of the invention for the resolution of compounds of formulaeII or III with a compound of formula I comprises reacting a compound ofthe formula ##STR16## wherein X is selected from the group consisting ofhydrogen and alkyl of 1 to 4 carbon atoms and A has the above definitionin the presence of an acid with an substituted alcohol or phenol of theformula

    ZOH                                                        III

wherein Z has the above definition to obtain either a mixture ofdiastereoisomers designated I_(B) when the lactone is a well definedoptical isomer and the chiral centers of the alcohol or phenol do nothave an unequivocal configuration or a mixture of diastereoisomersdesignated I_(C) when the alcohol or phenol is a well defined opticalisomer and the chiral atoms of the lactone do not have an unequivocalconfiguration, separating by physical methods the diastereoisomericethers contained in mixtures I_(B) or I_(C) to obtain particularly etherdesignated I_(A) in which the chiral centers have an unequivocalconfiguration and subjecting each of the so separated ethers tohydrolysis or an alcoholysis in an acid medium to obtain either acompound of type II and the other diastereoisomers eventually arisingdue to the existence of more asymetric centers or a compound of type IIIand the other diastereoisomers eventually arising due to the existenceof more asymetric centers, those compounds of formulae II and III andthe corresponding diverse diastereoisomers, containing chiral centers ofunequivocal configuration, in other words the resolved chiral centersdue to the corresponding chiral centers of the starting phenols oralcohols or due to the chiral centers of the starting lactone compounds.

The acid solvolysis of compounds of Type I_(A) (diastereoisomers ofunequivocal configuration) which results from the diastereoisomermixtures I_(B) or I_(C) permits the obtention of the alcohol or phenolof formula III as well as the lactone of formula II, each in its opticalisomer form, that is to say all the configuration of the chiral centersare exactly defined as (R) or (S).

By the application of this process in which the starting alcohol whichcomprises a single chiral center is a racemate formed by 2 antipodes (R)and (S) one can, by opposing it with a well defined optical isomer oflactone II, obtain 2 ethers of the Type I_(A) named respectively I_(D)and I_(E) that can be separated by a physical treatment, especially bycrystallization or chromatography. In the compounds I_(D) and I_(E), thealcohol moiety presents an antipodal configuration. By acid solvolysisof either I_(D) or I_(E), one can recover the alcohol ZOH resolved intoits antipodes (R) and (S), respectively.

By starting with a lactone having chiral centers presentingconfigurations corresponding to a racemate and being opposed with a welldefined optical isomer of an alcohol or phenol of formula III, one alsoobtain 2 ethers of type I_(A) named I_(F) and I_(G), respectively, whichcan be separated by physical methods, especially by chromatography orcrystallization. In the compounds I_(F) and I_(G), the lactone moietypresents an antipodal configuration and acid solvolysis of either I_(F)or I_(G) results in the lactone II resolved into its two antipodes.

A preferred process of the invention comprises reacting the lactone ofcis 2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid inthe presence of an acid agent with1(RS)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-en-4-one to obtaina mixture of (1R,5S)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,crystallizing the 1(S) isomer from isopropanol and subjecting the 1(S)isomer to acid solvolysis to obtain1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-en-4-one. The IRisomer may also be subjected to acid solvolysis to obtain1(R)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-en-4-one. The acidsolvolysis is preferrably effected in an aqueous medium in the presenceof hydrochloric acid or in methanol in the presence of p-toluenesulfonic acid.

Another modification of the process of the invention comprises reactingin the presence of an acid agent the lactone of dl cis2,2-dimethyl-3-(dihydroxymethyl)-cyclopropane-1-carboxylic acid with1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-3-en-4-one to form amixture of (1R, 5S)6,6-dimethyl-4(S)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxa-bicyclo-(3,1,0)-hexan-2-oneand (1R, 5S)6,6-dimethyl-4(R)-/1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy/-3-oxa-bicyclo-(3,1,0)-hexan-2-onecrystallizing the 4(S) isomer from isopropyl ether and subjecting thelatter to acid solvolysis to obtain the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid. Thepreferred acid agent is hydrochloric acid.

Another mode of the process comprises reacting the lactone of cis2,2-dimethyl-3S-(dihydroxy-methyl)-cyclopropane-1R-carboxylic acid inthe presence of an acid agent with2(R,S)-hydroxy-3,3-dimethyl-butyrolactone to obtain a mixture of (1R,5S)6,6-dimethyl-4(R)-[3',3'-dimethylbutyrolactone-2'(S)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1R, 5S)6,6-dimethyl-4(R)-[3',3'-dimethylbutyrolactone-2'(R)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,separating the isomers chromatography and subjecting one or the otherisomer to acid solvolysis to obtain either2(S)-hydroxy-3,3-dimethylbutyrolactone or2(R)-hydroxy-3,3-dimethylbutyrolactone from the 2'(S) or 2'(R) ether,respectively. Preferably, the acid solvolysis is effected with p-toluenesulfonic acid in an aqueous medium or methanol.

An additional modification of the process of the invention comprisesreacting (3R, 3aR, 4S, 7R, 7aS)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with (R,S) mentholin the presence of an acid agent to obtain a mixture of (3R, 3aR, 4S,7R, 7aS) 3-[(1'R), (2'S), (5'R)2-isopropyl-5'-methyl-cyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-oneand (3R, 3aR, 4S, 7R, 7aS) 3-[(1'S), (2'R), (5'S)2'-isopropyl-5'-methyl-cyclohexanoxy]-tetrahydro-4,7-methanoisobenzofuran-1-one,separating the said isomers by chromatography and subjecting one or theother isomer to acid solvolysis to obtain (R) or (S) menthol.

Another preferred modification of the process of the invention comprisesreacting the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid in thepresence of an acid agent with (R,S)-menthol to obtain a mixture of (1R,5S) 6,6-dimethyl-4(R)-[(1'R), (2'S), (5'R)2'-isopropyl-5'-methyl-cyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1R, 5S) 6,6-dimethyl-4(R)-[(1'S), (2'R), (5'S)2'-isopropyl-5'-methyl-cyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,separating the said isomers by chromatography and subjecting one or theother of the isomers to acid solvolysis to obtain either (R) or(S)-menthol. The solvolysis is preferably effected with p-toluenesulfonic acid in an aqueous medium.

There are a few known general procedures for the resolution of alcoholscontaining asymetric carbon atoms. For example, it is known to reactcertain (R,S) racemic alcohols with an optically active organic acid andthen to separate by any convenient physica method the ester of the (S)alcohol and the ester of the (R) alcohol and to subject the individualesters to hydrolysis to obtain the alcohol of (R) or (S) structure.

A more complicated resolution process is also known where the (R,S)racemic alcohol is reacted with an organic diacid to obtain a mixture ofhemiesters which is then reacted with an optically active base toseparate the corresponding diastereoisomeric salts, subjecting the saidindividual salts to acidification to obtain the hemiesters of the (S)alcohol and off the (R) alcohol and subjecting the individual hemiestersto hydrolysis to recover the alcohol of (R) or of (S) configuration.

However, these types of resolution can only be applied withoutdifficulty to sufficiently stable alcohols, insensible or slightlyinsensible to conditions of formation and hydrolysis of the intermediateesters of hemiesters.

The process of the present invention provides a novel, very generalmethod of resolution of substituted alcohols or phenols of formula IIIcontaining one or more asymetrical carbon atoms which method does nothave the inconveniences of the prior art methods. This novel methodusing the diverse steps discussed above consists of reacting thesubstituted alcohol or phenol of formula III containing at least oneasymetrical carbon atoms of (R,S) configuration in the presence of anacid agent with an optical isomer of a lactone of formula II possessingone or more chiral atoms of well definite steric configuration (R) or(S) to obtain an equimolar mixture of diastereoisomers of type I_(A) inwhich the radical (Z) possesses an unequivocal stereochemistry due toeach chiral center. The diastereoisomers of type I_(A) may be separatedby physical methods such as chromatography or crystallization from asolvent and then subjecting the individual diastereoisomers of typeI_(A) to solvolysis in an acid medium to obtain, respectively, thesubstituted alcohol or phenol of formula III with an unequivocalstereochemistry.

This method has the advantage over other known resolution methods ofgreater simplicity than the prior art in the steps of reacting thesubstituted alcohols or phenols of formula III with the lactone offormula II which is used in the form of an optical isomer of determinedstereochemistry to obtain the corresponding diastereoisomeric ethers oftype I_(B) which are separated by physical methods into compounds oftype I_(A) which have a well defined stereochemistry and then subjectingeach of the compounds of type I_(A) to acid solvolysis to obtain theresolved substituted alcohols or phenols of formula III.

The resolution method of the invention has a very general applicationsince the reaction of the compound of formula III with an optical isomerof formula II is effected in very good yields and the resulting ethersgenerally possess a structure wherein the separation by physical meansof stereoisomers of type I_(A) is easy. The separation may be effectedby crystallization from any convenient solvent and the solvolysis of thediastereoisomers of type I_(A) in acid media leads without difficultyand in good yields to the resolved substituted alcohols or phenols offormula III.

The final solvolysis may be effected without any notable alteration ofthe compound of formula III and the stereochemistry of the compounds offormula II is maintained during the solvolysis only if the structure ofthe compounds of formula II imposes to the hydroxyl an unequivocaldisposition. The resolution process of the invention is especiallyuseful for extremely fragile or sensitive alcohols such as cyanhydrins.

This method of resolution of substituted alcohols or phenols generallyis widely used to permit obtaining in the majority of cases and underadvantageous conditions starting from racemic compounds obtained bychemical synthesis, the resolved optical isomers of which one of themgenerally has the quasi totality of activity of the concerned molecule(case of natural compounds which are optionally active).

In the above discussions, it is also a point that there is a new methodof resolving lactonic compounds of formula II containing one or morechiral atoms. This new method consists of reacting in the presence of anacid agent a lactone of formula II containing at least one chiral atomof (R,S) racemic configuration with an optical isomer of an substitutedalcohol or phenol of formula III of determined steric configuration (R)or (S) to obtain a mixture of diastereoisomeric ethers of type I_(C),subjecting the said mixture to a physical treatment such aschromatography or crystallization to separate the diastereoisomers oftype I_(A) contained in the mixture, each diastereoisomer presenting inthe lactone moiety a well defined stereochemistry, and subjecting thesecompounds to hydrolysis in an acid media to obtain the compound offormula II in resolved form. This method, which is not described in theliterature, presents in a general manner the same advantages and thesame simplicity of the resolution of the substituted alcohols or phenolsdescribed above.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1 Mixture of (1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1R,5S),6,6-dimethyl-4(R)-[1(R)-2methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

A mixture of 3.5 g of p-toluene sulfonic acid, 152 g of(1RS)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-en-4-one and 1000ml of benzene was refluxed for 4 hours while azeotropically removing thewater of reaction and the mixture was cooled to 20° C. The pH of themixture was adjusted to 7-8 by addition of triethylamine and the mixturewas evaporated to dryness under reduced pressure to obtain a mixture of(1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo(3,1,0)-hexan-2-oneand (1R,5S)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one.

EXAMPLE 2 (1R,5S)6,6-dimethyl-4-(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

The mixture of Example 1 was added to 300 ml of isopropanol and themixture was stirred at 0° C. and was then vacuum filtered. The recoveredproduct was washed and dried to obtain 82.6 g of (1R,5S)6,6-dimethyl-4-(R)-[1-(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-onemelting at 104° C. and having a specific rotation of [α]_(D) ²⁰ =66.5°C. (c=1.1% in benzene).

Analysis: C₁₆ H₂₀ O₄ ; molecular weight=276:

Calculated: %C, 69.54, %H 7.3:

Found: 69.3, 7.4.

Circular dichroism (dioxane):

Δε=-26.4 at 222 nm (max.); Δε=+2.8 at 321 nm (max.);

Δε=+2.50 at 332 nm (max.)

RMN Spectrum (deuterochloroform): peaks at 1.22 ppm (hydrogen of geminalmethyls); at 1.97 to 2.33 ppm (hydrogens of cyclopropane ring); at 2.1ppm (hydrogens of 2-methyl of allethrolene); at 2.92-3.02 ppm(1-methylene of allyl of allethrolone); at 4.63 ppm (1-hydrogen ofallethrolone); at 4.75-5.17 ppm (hydrogens of terminal methylene in3-position of allyl of allethrolone); at 5.33 ppm (hydrogen on carbon αto endocyclic oxygen); at 5.47-6.16 ppm (2-hydrogen of allyl ofallethrolone).

EXAMPLE 3 (1R,5S)6,6-dimethyl-4-(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

A mixture of 7.5 g of the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid, 7.5 gof 1(R)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one, 0.100g of p-toluene sulfonic acid and 75 ml of benzene was refluxed for 4hours while the water of reaction was azeotropically distilled off andwas then evaporated to dryness under reduced pressure to obtain 15 g of(1R,5S)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one.

Circular dichroism (dioxane):

Δε=2.56 at 330 nm (max.); Δε=-2.8 at 316 nm (max.); Δε=+14.6 at 225 nm(max.).

RMN Spectrum (deuterochloroform): peaks at 1.22-1.23 ppm (hydrogens ofgeminal methyls); at 2.07 ppm (hydrogens of 2-methyl of allethrolone);at 2.92-3.02 ppm (hydrogens of 1-methylene of allyl of allethrolone); at4.83-5.08 ppm (hydrogens of 3-methylene of allyl of allethrolone); at4.87 ppm (1-hydrogen of allethrolone); at 5.26 ppm (hydrogen on carbon αto endocyclic oxygen); at 5.47-6.33 ppm (2-hydrogen of allyl ofallethrolone).

EXAMPLE 4 (1R,5S6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

A mixture of 5 g of the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid, 5 gof 1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one, 0.05 gof p-toluene sulfonic acid and 30 ml of petroleum ether (b.p.=35°-75°C.) was refluxed with stirring for 4 hours while azeotropically removingthe water of reaction and after cooling the mixture to 0° C., themixture was stirred and vacuum filtered. The recovered product waswashed and dried to obtain 8.7 g of (1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-onemelting at 104° C. The mother liquors were evaporated to dryness and theresidue was crystallized from isopropanol to obtain another 0.12 g ofthe said product.

EXAMPLE 5 (1R,5S) 6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

In a receptable mounted over a system for azeotropic decantation, amixture of 25.2 g of1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one-[(S)-allethrolone],23.5 g of the lactone of dl cis2,2-dimethyl-3-(dihydroxymethyl)-cyclopropane-1-carboxylic acid, 0.25 gof p-toluene sulfonic acid and 250 ml of benzene was refluxed withstirring while eliminating by azeotropic decantation the water ofreaction for 4 hours. The mixture was cooled and was neutralized withtriethylamine. The mixture was evaporated to dryness under reducedpressure and 5 ml of isopropyl ether were added to the residue. Themixture was stirred at 0° C. for one hour and was vacuum filtered. Therecovered product was washed and dried to obtain 15.1 g of (1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-onemelting at 104° C.

EXAMPLE 61(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one-or(S)allethrolone

A mixture of 82.6 g of the product of Example 4, 826 ml of water and 8.2ml of aqueous 22° Be hydrochloric acid was stirred at 20° C. for 72hours and the pH of the resulting solution was adjusted to 10.5 byaddition of aqueous N sodium hydroxide. The mixture was extracted withmethylene chloride and the organic phase was dried and evaporated todryness under reduced pressure to obtain 42.9 g of1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one with aspecific rotation of [α]_(D) ²⁰ =+14° (c=1.2% in chloroform).

Circular dichroism (dioxane): Δε=-20 at 230 nm (max.); Δε=+3.36 at 321nm (max.); Δε=+3.0 at 331 nm (max.).

EXAMPLE 7 (R)-allethrolone

A mixture of 82.4 g of the product of Example 3, 824 ml of water and 8.2ml of aqueous 22° Be hydrochloric acid was stirred for 72 hours at 20°C. and the pH of the resulting solution was adjusted to 10.5 by additionof aqueous N sodium hydroxide. The mixture was extracted with methylenechloride and the organic phase was dried and evaporated to dryness underreduced pressure to obtain 42.7 g of (R)-allethrolone with a specificrotation of [α]_(D) ²⁰ =-14.5° (c=1.2% in chloroform).

Circular dichroism (dioxane): Δε=+20 at 230 nm (max.); Δε=-3.36 at 321nm (max.); Δε=-3.0 at 331 nm (max.).

EXAMPLE 8 (S)-allethrolone

A mixture of 8.3 g of the product of Example 3, 0.83 g of p-toluenesulfonic acid and 42 ml of methanol was stirred at 20° C. for 2 hoursand the pH was then adjusted to 7 by addition of sodium carbonate. Themixture was filtered and the filtrate was evaporated to dryness underreduced pressure. The 10 g of residue was chromatographed over silicagel and was eluted with a 7-3 benzene-ethyl acetate mixture to obtain4.4 g of (S)-allethrolone with a specific rotation of [α]_(D) ²⁰ =+14.5°(c=1.2% in chloroform).

Circular dichroism (dioxane): Δε=-20.4 at 229 nm (max.); Δε=+3.36 at 321nm (max.); Δε=+3.08 at 331 nm (max.).

EXAMPLE 9 Lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid

A mixture of 2.76 g of the product of Example 5, 1 ml of aqueous 22° Behydrochloric acid and 100 ml of water was stirred for 72 hours and thepH of the solution was adjusted to 10 by addition of aqueous N sodiumhydroxide. The basic aqueous phase was extracted with methylene chlorideand the organic phase was washed with water, dried and evaporated todryness under reduced pressure to obtain 1.39 g of (S) allethrolone. Theaqueous phase was saturated with ammonium sulfate and was then acidifiedby addition of hydrochloric acid. The mixture was stirred for one hourand was vacuum filtered. The insoluble gum residue was dissolved inethyl acetate and the mixture was filtered. The filtrate was evaporatedto dryness to obtain 1.32 g of the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid.

EXAMPLE 10 (3R, 3aR, 4S, 7R,7aS)-3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 4.3 g of (3R, 3aR, 4S, 7R,7aS)-3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one of Example 24,3.9 g of1-(R,S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one, 40 mgof p-toluene sulfonic acid and 50 ml of anhydrous benzene was refluxedfor 18 hours and was then evaporated to dryness under reduced pressure.The residue was chromatographed over silica gel and was eluted with a100-2.5 chloroform-acetone mixture to obtain a 2.4 g of (3R, 3aR, 4S,7R,7aS)-3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-onein the form of an oil.

EXAMPLE 11 (3R, 3aR, 4S, 7R,7aS)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one

Following the chromatography of Example 10, there were obtained 2.7 g of(3R, 3aR, 4S, 7R,7aS)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-onein the form of white crystals melting at 148° C.

EXAMPLE 12 (3R, 3aR, 4S, 7R,7aS)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer A) and (3S, 3aS, 4R, 7S,7aR)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer B) STEP A: 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 30 g of 5-hydroxy-2(5H)-furanone, 150 ml of chloroform, 50mg of hydroquinone and 35 ml of freshly distilled cyclopentadiene wasstirred at 20° C. under an inert atmosphere and stirred for 17 hours at20°-45° C. The mixture was evaporated to dryness under reduced pressureand the residue was crystallized from an isopropyl ether-petroleum ethermixture to obtain 46.6 g of3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one melting point at≃103° C.

Analysis: C₉ H₁₀ O₃ ; molecular weight=166.17: Calculated: %C 65.06, %H6.06: Found: 65.3, 6.2.

I.R. Spectrum (CHCl₃): 3580 cm⁻¹ (OH); 1770 cm⁻¹ (C=O)

RMN Spectrum (deuterochloroform): peaks at 6.2-6.22 ppm (ethylenichydrogens); at 5.18-5.27 ppm (1-hydrogen); at 4.87-4.95 ppm (hydrogen of1-hydroxyl); at 1.33 to 1.75 ppm (hydrogens of methylene).

STEP B: (3R, 3aR, 4S, 7R,7aS)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer A) and (3S, 3aS, 4R, 7S,7aR)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer B)

A mixture of 33 g of racemic3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 30 g of(S)-allethrolone, 0.18 g of p-toluene sulfonic acid and 200 ml ofbenzene was refluxed for 4 hours and was evaporated to dryness underreduced pressure. The 60.3 g of residue were chromatographed over silicagel and was eluted with a 100-5 chloroform-acetone mixture to obtain17.4 g of (3R, 3aR, 4S, 7R,7aS)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer A) melting at 148° C. and a specific rotation of [α]_(D) ²⁰ =-8°(c=1.5% in benzene) and 13.6 g of (3S, 3aS, 4R, 7S,7aR)-3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-onehaving a specific rotation [ α]_(D) ²⁰ =+42.5° (c=1% in benzene).

Isomer A

Analysis: C₁₈ H₂₀ O₄ ; molecular weight=300.36: Calculated: %C 71.98, %H6.71: Found: 72.0, 6.8:

I.R. Spectrum (chloroform): Absorption at 1775 cm⁻¹ (lactone); at 1700cm⁻¹ (carbonyl); at 1657 cm⁻¹, 1640 cm⁻¹ (conjugated ethylenic doublebond); at 981-918 cm⁻¹ (vinyl).

Circular dichroism (dioxane): Δε=-18.3 at 225 nm (max.); Δε=+2.29 at 321nm (max.); Δε=+2.59 at 332 nm (max.).

RMN Spectrum (deuterochloroform): peaks at 6.25-6.28 ppm (ethylenichydrogens of lactone 5,6); at 5.1 ppm (3-hydrogen of lactone); at 1.33to 1.75 ppm (hydrogens of 8-CH₂ of lactone); at 4.58 (1-hydrogen ofallethrolone ring); at 2.07 ppm (hydrogens of 2-methyl of allethrolonering); at 5.17 to 6.33 ppm (2'-hydrogens of propenyl); at 4.83 to 5.13ppm (3'-hydrogens of propenyl).

Isomer B

Analysis: C₁₈ H₂₀ O₄ ; molecular weight=300.36 Calculated: %C 71.98, %H6.71: Found: 71.8, 6.7.

I.R. Spectrum (chloroform): absorption at 1770 cm⁻¹ (carbonyl); at 1706cm⁻¹ (conjugated carbonyl); at 1656-1640 cm⁻¹ (conjugated ethylenicdouble bond); at 982-918 cm⁻¹ (vinyl).

Circular dichroism (dioxane): Δε=-18.4 at 226 nm (max.); Δε=+2.9 at 319nm (max.); Δε=+2.63 at 331 nm (max.).

RMN Spectrum (deuterochloroform): peaks at 6.25-6.28 ppm (5,6 ethylenichydrogens of lactone); at 5.0 ppm (3-hydrogen of lactone); at 1.33 to1.75 ppm (hydrogens of 8-CH₂ of lactone); at 4.73 ppm (1-hydrogen ofallethrolone ring); at 2.03 ppm (hydrogens of 2-methyl of allethrolone);at 5.33-6.33 ppm (2'-hydrogen of propenyl); at 4.83 to 5.13 ppm(3'-hydrogens of propenyl).

EXAMPLE 13 (3S, 3aS, 4R, 7S, 7aR) 3-[(1R)2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer D) and (3R, 3aR, 4S, 7R, 7aS)3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer C)

A mixture of 18.4 g of racemic3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 16 g of(R)-allethrolone, 0.10 g of p-toluene sulfonic acid monohydrate and 100ml of anhydrous benzene was refluxed for 18 hours and was thenevaporated to dryness under reduced pressure. The 31.4 g of residue waschromatographed over silica gel and was eluted with a 100-5chloroform-acetone mixture to obtain 9.4 g of (3S, 3aS, 4R, 7S, 7aR)3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(isomer D) in the form of white crystals melting at 148° C. and having aspecific rotation of [α]_(D) ²⁰ =+11.5°±1° (c=1% in benzene) and 11.7 gof (3R, 3aR, 4S, 7R, 7aS) 3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methao-isobenzofuran-1-one(isomer C) in the form of a gummy crystal and having a specification of[α]_(D) ²⁰ =51°±1° (c=1% in benzene).

Isomer D

RMN Spectrum (deuterochloroform): peaks at 6.23 ppm (ethylenic hydrogensof lactone 5,6); at 1.33-1.75 ppm (hydrogens of 8-CH₂ of lactone); at5.0 ppm (3-hydrogen of lactone); at 4.5-4.58 ppm (1-hydrogen ofallethrolone ring); at 2.06 ppm (hydrogens of CH₃ of allethrolone).

I.R. Spectrum (CHCl₃): absorption at 1775 cm⁻¹ (carbonyl of lactone); at1700 cm⁻¹ (conjugated carbonyl); at 1657-1640 cm⁻¹ (C═C and conjugated).

Circular dichroism (dioxane): In accord with ether of (R) allethrolone,curve practically antipodal to isomer A of Example 12-Δε=+23.0 at 225 nm(max.); Δε=-3.0 at 320 mm (max.); Δε=-2.69 at 332 nm (max.).

Isomer C

Circular dichroism (dioxane): In accord with ether of(R)-allethrolone-curve practically antipodal to isomer of B of Example12--Δε=+19.1 at +224 nm (max.); Δε=-2.88 at 318 nm (max.); Δε=-2.59 at330 nm (max.).

RMN Spectrum (deutrochloroform): peaks at 6.26 ppm (ethylenic hydrogensof lactone copule); at 1.33-1.75 ppm (hydrogens of 8-CH₂ of lactonecopule); at 5.0 ppm (1-hydrogen of lactone copule); at 4.7 ppm(1-hydrogen of allethrolone ring); at 2.0 ppm (hydrogen of CH₃ ofallethrolone ring); at 5.33-6.33 ppm (2'-hydrogen of propenyl); at4.83-5.1 ppm (3'-hydrogen of propenyl).

I.R. Spectrum (CHCl₃): absorption at 1770 cm⁻¹ (lactone carbonyl); at1706 cm⁻¹ (conjugated carbonyl); at 1656-1640 cm⁻¹ (C═C and conjugated).

EXAMPLE 14 (1R, 5S)6,6-dimethyl-4(R)-[3',3'-dimethyl-butyrolactone-2'-(S)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(compound A) and (1R, 5S) 6,6-dimethyl-4(R)-[3',3'-dimethylbutyrolactone-2'-(R)-oxy]-3oxa-bicyclo-(3,1,0)hexane-2-one-(compound B)

A mixture of 7 g of pantolactone. 7.1 g of the lactone of2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid, 140mg of p-toluene sulfonic acid and 50 ml of benzene was stirred under aninert atmosphere and was then refluxed for 71/4 hours. The benzene wasevaporated at 40° C. under reduced pressure and the residue waschromatographed over silica gel. Elution with an 85-15 benzene-ethylacetate mixture yielded 2.956 g of (1R, 5S) 6,6-dimethyl-4(R)-[3',3'-dimethylbutyrolactone-2'(S)-oxy]-3-oxabicyclo-(3,1,0)-hexane-2-onemelting at 102°-104° C. (compound A) and then 547 mg of (1R,5S)6,6-dimethyl-4(S)-[3',3'-dimethyl-butyrolactone-2'(R)-oxy]-3-oxabicyclo-3,1,0)hexan-2-onemelting at 134° C. and finally 1.654 g of(1R,5S)6,6-dimethyl-4(R)-[3',3'-dimethylbutyrolactone-2'(R)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one melting at 120° C. (Compound B).

RMN Spectrum (deuterochloroform): Compound A--peaks at 4.00 ppm(4'-hydrogens of pantolactone); at 4.2 ppm (2'-hydrogen ofpantolactone); at ≃5.7 ppm (4-hydrogen of bicyclo (3,1,0)hexanone); at2-2.1 and 2.22-2.31 ppm (1- and 3-hydrogens of cyclopropyl); at 1.1-1.22ppm (hydrogens of methyls). Compound B--peaks at 4.0 ppm (4'-hydrogensof pantolactone); at 4.23 ppm (2'-hydrogen of pantolactone); at 5.47 ppm(4-hydrogen of bicyclo(3,1,0) hexanone); at 2.06-2.15 and 2.36-2.45 ppm(1- and 3-hydrogens of cyclopropyl); at 1.12-1.2-1.24 ppm (hydrogens ofmethyls).

EXAMPLE 15 Racemic mixture of (3S, 3aR, 4S, 7R, 7aS)3[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-oneand (3R, 3aS, 4R, 7S, 7aR)3-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 66 g of racemic3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 60 g of1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-one, 300 mg ofp-toluene sulfonic acid and 600 ml of benzene was refluxed for 3 hoursand the mixture was neutralized with 4 ml of triethylamine. The mixturewas evaporated to dryness and the residue was taken up in isopropylether. The mixture was vacuum filtered to recover 23 g of (3R, 3aR, 4S,7R, 7aS)3-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(compound A) melting at 148° C. The mother liquors were chromatographedover silica gel and elution with a 100-5 chloroform-acetone mixtureyielded first 28.8 g of (3S, 3aS, 4R, 7S, 7aR)3-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(compound B), then 26 g of compound A and finally 16 g of a mixture ofracemic mixture of (3S, 3aR, 4S, 7R, 7aS)3-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methanoisobenzofuran-1-oneand (3R, 3aS, 4R, 7S, 7aR)3-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-onecompounds.

I.R. Spectrum (CHCl₃): absorption at 1764 cm⁻¹ (γ-lactone); at 1708,1655 and 1639 cm⁻¹ (allethrolone).

RMN Spectrum (deuterochloroform): peaks at 6.17 ppm (5,6-ethylenichydrogens); at 2.92 to 3.42 ppm (3a, 4,7 and 7a hydroens); at 1.33-1.48and 1.55-1.7 ppm (8-hydrogens); at 5.58 to 5.75 ppm (3-hydrogen); at 4.5to 4.83 ppm (1'-hydrogen of allethrolone); at 2.07 ppm (hydrogens of2'-methyl of allethrolone); at 5.52 to 6.17 ppm (2-hydrogen ofpropenyl); at 4.83 to 5.17 ppm (3-hydrogens of propenyl).

EXAMPLE 16 (1R,5S)6,6-dimethyl-4(R)-[(R)-ethynyl-(3'-phenoxyphenyl)-methoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(isomer R)

A mixture of 20 g of the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid, 30 gof racemic ethynyl-(3'-phenoxyphenyl)-methanol, 200 mg of p-toluenesulfonic acid and 200 ml of benzene was refluxed with stirring for onehour while azeotropically removing the water of reaction and aftercooling to 20° C., the mixture was neutralized with triethylamine. Themixture was evaporated to dryness under reduced pressure and the 51 g ofbrown oil residue was chromatographed under pressure. Elution with a95-5 benzene-ethyl acetate mixture obtained 10.7 g of (1R, 5S)6,6-dimethyl-4(R)-[(R)-ethynyl-(3'-phenoxyphenyl)-methoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(isomer R) in the form of an oil.

RMN Spectrum (deuterochloroform): peaks at 1.16-1.25 ppm (hydrogens ofgeminal methyls); at 5.65 ppm (4-hydrogen); at 2.68-2.7 ppm (hydrogen ofethynyl); at 5.50-5.52 ppm (hydrogen of carbon attached to ethynyl); at6.83 to 7.50 ppm (hydrogens of aromatic ring); at 1.95-2.03 and 2.1-2.18ppm (hydrogens of cyclopropyl).

EXAMPLE 17 (1R, 5S)6,6-dimethyl-4(R)-[(S)-ethynyl-(3'-phenoxyphenyl)-methoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(isomer S)

Following the chromatography under pressure of Example 16, there wasobtained 10.4 g of (1R, 5S)6,6-dimethyl-4(R)-[(S)-ethynyl-(3'-phenoxyphenyl)-methoxy]-3-oxabicyclo(3,1,0)-hexan-2-one(isomer S) in the form of an oil and then 8.4 g of a mixture of the saidR and S isomers.

RMN Spectrum (deuterochloroform): isomer S peaks at 1.11 ppm (hydrogensof geminal methyls); at 5.05 ppm (4-hydrogen); at 2.65-2.68 ppm(hydrogen of ethynyl); at 5.41-5.45 ppm (hydrogen of carbon attached toethynyl); at 2.05 ppm (hydrogens of cyclopropyl).

EXAMPLE 18 (1R, 5S)6,6-dimethyl-4(R)-[3'-methyl-2'(R)-butoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

A mixture of 28 g of the lactone of cis2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-1R-carboxylic acid, 25 mlof racemic 3-methyl-2-butanol, 100 mg of p-toluene sulfonic acid and 100ml of benzene was refluxed with stirring for 2 hours whileazeotropically removing the water of reaction and after cooling themixture to 20° C., it was neutralized with triethylamine. The mixturewas evaporated to dryness under reduced pressure and the 44 g of oilresidue was chromatographed over silica gel to obtain 33 g of a mixtureof 2 diastereoisomers. The latter was chromatographed over silica gelunder pressure and elution with methylene chloride containing 2% ofacetonitrile yielded 160 mg of (1R, 5S)6,6-dimethyl-4(R)-[3'-methyl-2'(R)-butoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(isomer R) with a melting point of 19-21° C. and a specific rotation of[α]_(D) ²⁰ =-143°±3.5° (c= 0.5% in benzene).

RMN Spectrum (deuterochloroform): peaks at 1.15-1.17 ppm (hydrogens ofgeminal methyls); at 5.25 ppm (4-hydrogen); at 1.07-1.17 ppm (hydrogensof 1'-methyl of propyloxy); at 3.45 to 3.87 ppm (1'-hydrogen ofpropyloxy); at 0.83 to 0.93 ppm (hydrogens of 2'- and 3'-methyls ofpropyloxy).

EXAMPLE 19 (1R, 5S)6,6-dimethyl-4(R)-[3'-methyl-2'-(S)-butoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one

After the recovery of isomer A in Example 18, elution was continued toobtain 57 mg of (1R, 5S)6,6-dimethyl-4(R)-[3'-methyl-2'(S)-butoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(isomer S) with a melting point of ≃35° C. and a specific rotation of[α]_(D) ²⁰ =-121°±3.5° (c=0.5% in benzene).

RMN Spectrum (deuterochloroform): peaks at 1.17-1.19 ppm (hydrogens ofgeminal methyls); at 5.2 ppm (4-hydrogen); at 3.38 to 3.46 ppm(1'-hydrogen of propyloxy); at 0.83-0.95 ppm (hydrogens of 2' and3'-methyls of propyloxy); at 1.15-1.25 ppm (hydrogens of 1'-methyl).

EXAMPLE 20 (3S, 3aS, 4R, 7S, 7aR)3-[1(R)-(3'-phenoxyphenyl)-α-methylmethoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 300 mg of (3S, 3aS, 4R, 7S, 7aR)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 400 mg of1(R)(3'-phenoxyphenyl)-α-methyl-methanol, 30 mg of p-toluene sulfonicacid and 30 ml of benzene was refluxed for 90 minutes and was thencooled to 20° C. and neutralized with triethylamine. The mixture wasevaporated to dryness under reduced pressure and the oil residue waschromatographed over silica gel. Elution with a 9-1 benzene-ethylacetate mixture yielded 400 mg of (3S, 3aS, 4R, 7S, 7aR)3-[1(R)-(3'-phenoxyphenyl)-α-methyl-methoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(product F) melting at 146° C.

RMN Spectrum (deuterochloroform): peaks at 1.3-1.65 ppm (hydrogens of8-CH₂); at 5.83-6.25 ppm (ethylenic hydrogens); at 4.7 ppm (3-hydrogen);at 1.37-1.48 ppm (hydrogens of α-methyl); at 4.58-4.7-4.82-4.93 ppm(1'-hydrogen of alcohol copule); at 6.83-7.5 ppm (hydrogens of aromaticring).

Circular dichroism (dioxane): Δε=+1.9 at 235 nm (max.); Δε=+0.58 at 257nm (Inflex.); Δε=+0.77 at 263 nm (max.); Δε=-1.67 at 276 nm (max.);Δε=-2.00 at 281 nm (max.); structure R at the level of ##STR17##

EXAMPLE 21 (3S, 3aS, 4R, 7S, 7aR)3-[1(S)-(3'-phenoxyphenyl)-α-methylmethoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 300 mg of (3S, 3aS, 4R, 7S, 7aR)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 400 mg of1(S)-(3'-phenoxyphenyl)-α-methyl-methanol, 30 mg of p-toluene sulfonicacid and 15 ml of benzene was refluxed with stirring for 90 minutes andafter cooling, the mixture was evaporated to dryness under reducedpressure to obtain 900 mg of a thick oil. The latter was chromatographedover silica gel and was eluted with a 95-5 benzene-ethyl acetate mixtureto obtain 400 mg of (3S, 3aS, 4R, 7S, 7aR)3-[1(S)-(3'-phenoxyphenyl)-α-methyl-methoxy]-tetrahydro-4,7-methano-isobenzofuran-1-onemelting at 78°-79° C.

I.R. Spectrum (CHCl₃): absorption at 1769 cm⁻¹ (C=0 α-lactone); at1587-1490 cm⁻¹ (aromatic rings); at 1250 cm⁻¹ (C-O-C); at 694 cm⁻¹(phenyl ring).

Circular dichroism (dioxane): Δε=0.8 at 281 nm (max.); Δε=+0.6 at 275 nm(max.); Δε˜-2.5 to -3 at ≃225 nm (max.). -compatible with Sconfiguration of alcohol moiety.

RMN Spectrum (deuterochloroform): peaks at 6.2 ppm (ethylenichydrogens); at 1.33-1.75 ppm (hydrogens of 8-CH₂); at 5.07 ppm(3-hydrogen); at 1.4-1.5 ppm (hydrogens of α-methyl); at 4.6-4.7-4.8 ppm(hydrogen of carbon attached to α-methyl); at 6.7-7.5 ppm (hydrogens ofatomatic ring); at 2.67 to 3.5 ppm (other protons).

EXAMPLE 22 1(S)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-oneor (S) allethrolone

A mixture of 2.7 g of (3R, 3aR, 4S, 7R, 7aS)3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one,0.25 g of p-toluene sulfonic acid monohydrate, 30 ml of water and 20 mlof dioxane was refluxed for 24 hours and then the solvent was evaporatedunder reduced pressure. The mixture was neutralized with triethylamineto a pH of 7 and was then evaporated to dryness under reduced pressure.The 2.8 g of residue was chromatographed over silica gel and was elutedwith a 1--1 benzene-ethyl acetate mixture containing 0.1% oftriethylamine to obtain 1 g of (S) allethrolone, 0.4 g of lactone and0.7 g of a mixture of (S) allethrolone-lactone. The (S) allethrolone hada specific rotation of [α]_(D) ²⁰ =+6.5°±1° (c=1.5% in benzene).

Circular dichroism (dioxane): Δε=-15.7 at 228 nm (max.); Δε=+2.46 at318-319 nm (max.); Δε=+2.26 at 330 nm (max.).

EXAMPLE 23 1(R)-hydroxy-2-methyl-3-(2-propen-1-yl)-cyclopent-2-ene-4-oneor (R)-allethrolone

Using the procedure of Example 22, (3R, 3aR, 4S, 7R, 7aS)3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-onewas reacted to obtain the same yield of (R)-allethrolone with a specificrotation of [α]_(D) ²⁰ =-6.5°±1° (c=0.8% in benzene).

Circular dichroism (dioxane): Δε=+17.3 at 228 nm (max.); Δε=-2.92 at 318nm (max.); Δε=-2.68 at 330 nm (max.).

EXAMPLE 24 (3R, 3aR, 4S, 7S, 7aS)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 12.8 g of (3R, 3aR, 4S, 7R, 7aS)3-[(1S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-1-one,1.2 g of p-toluene sulfonic acid monohydrate, 120 ml of water and 60 mlof dioxane was refluxed for 2 hours and was neutralized to a pH of 7with triethylamine. The mixture was evaporated to dryness under reducedpressure and the residue was chromatographed over silica gel. Elutionwith a 1--1 benzene-ethyl acetate mixture containing 0.1% oftriethylamine yield 5.3 g of (3R, 3aR, 4S, 7R, 7aS)3-hydroxy-tetrahydro-4,7-methanoisobenzofuran-1-one in the form of whitecrystals melting at 120° C. and a specific rotation of [α]_(D) ²⁰=+49.5° (c=1% in chloroform).

Analysis: C₉ H₁₀ O₃ ; molecular weight=166.17 Calculated: %C 65.05, %H6.07; Found: 65.0, 6.1.

Circular dichroism (dioxane): Δε=+2.57 at 218 nm (max.); Δε=-0.015 at292 nm (max.); Δε=+0.011 at 333 nm (max.); Δε=+0.006 at 345 nm (max.).

I.R. Spectrum (CHCl₃): absorption at 3580 cm⁻¹ (OH); at 1769-1740 cm⁻¹(C═O)

RMN Spectrum (deuterochloroform): peaks at 6.2 ppm (ethylenichydrogens); at 5.22-5.23 ppm (3-hydrogen); at 4.75 ppm (hydrogen ofhydroxyl); at 1.33-1.73 ppm (hydrogens of 8-CH₂); at 2.75-3.52 ppm(other protons).

EXAMPLE 25 (3S, 3aS, 4R, 7S, 7aR)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 1.9 g of (3S, 3aS, 4R, 7S, 7aR)3-[(1R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-tetrahydro-4,7-isobenzofuran-1-one,0.2 g of p-toluene sulfonic acid monohydrate, 20 ml of water and 20 mlof dioxane was refluxed for 6 hours and was neutralized to pH of 7 withtriethylamine. The mixture was evaporated to dryness under reducedpressure and the residue was chromatographed over silica gel. Elutionwith a 1--1 benzene-ethyl acetate mixture containing 0.1% oftriethylamine yielded 650 mg of (3S, 3aS, 4R, 7S, 7aR)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one melting at 120° C.and having a specific rotation of [α]_(D) ²⁰ =-47.5°±2.5° (c=1% inchloroform).

RMN Spectrum (deuterochloroform): peaks at 6.23 ppm (ethylenichydrogens); at 5.25 ppm (3-hyrogen); at 4.9 ppm (hydrogen of --OH); at1.35-1.5 and 1.6-1.75 ppm (hydrogens of 8-CH₂); at 2.83 to 3.58 ppm(other protons).

EXAMPLE 26 Racemic mixture of (3S, 3aR, 4S, 7R, 7aS)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one and (3R, 3aS, 4R,7S, 7aR) 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 15 g of the mixture obtained in Example 15, 75 ml ofdioxane, 150 ml of water and 1.5 g of p-toluene sulfonic acid wasrefluxed for 2 hours and after cooling the mixture, the pH was adjustedto 7-8 with triethylamine. The mixture was evaporated to dryness underreduced pressure and the residue was chromatographed over silica gel.Elution with a 1--1 benzene-ethyl acetate mixture containing 0.1% oftriethylamine yielded 4.85 g of racemic mixture of (3S, 3aR, 4S, 7R,7aS) 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one (3R, 3aS, 4R,7S, 7aR) 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with amelting point of 103° C.

RMN Spectrum (deuterochloroform): peaks at 6.2 ppm (ethylenichydrogens); at 5.22 ppm (3-hydrogen); at 1.33-1.48 and 1.55-1.7 ppm(hydrogens of 8-CH₂); at 4.67 ppm (hydrogen of OH); at 2.75 to 3.5 ppm(other protons). By circular dichroism at 218 nm of lactone chromophore,it was ascertained that the product was racemic.

EXAMPLE 27 (S) 1-(3-phenoxyphenyl)-prop-2-yn-1-ol

A mixture of 10.4 g of (1R, 5S)6,6-dimethyl-4(R)-[(S)-ethynyl-(3'-phenoxy-phenyl)-methoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,1 g of p-toluene sulfonic acid, 80 ml of water and 80 ml of dioxane wasrefluxed for 2 hours and was evaporated to dryness under reducedpressure. The residue was added to water and the mixture was stirred andwas extracted with isopropyl ether. The organic phase was subjected tothe usual treatment and was evaporated to dryness under reducedpressure. The 6 g of residue was chromatographed over silica gel and waseluted with a 7-3 benzene-ethyl acetate mixture to obtain 5.1 g of (S)1-(3-phenoxyphenyl)-prop-2-yn-1-ol with a specific rotation of [α]_(D)²⁰ =+10.5° (c=0.63% in benzene).

RMN Spectrum (deuterochloroform): peaks at 2.30 ppm (hydrogen of --OH);at 2.61-2.66 ppm (ethylenic hydrogens); at 5.44-5.50 ppm (hydrogen ofcarbon attached to ethynyl); at 6.91-7.0 ppm (hydrogens of aromaticring).

Circular dichroism (dioxane): Δε=+1.9 at 215 nm (max.); Δε=+0.02 at 272nm (max.); Δε=-0.01 at 276 nm (max.); Δε=+0.04 at 278 nm (max.);Δε=-0.03 at 283 nm (max.).

EXAMPLE 28 (R) 1-(3-phenoxyphenyl)-prop-2-yn-1-ol

Using the procedure of Example 27, 10.6 g of (1R, 5S)6,6-dimethyl-4(R)-[(R)-ethynyl-(3'-phenoxyphenyl)-methoxy]-3-oxabicyclo-(3,1,0)-hexan-2-onewere reacted to obtain 5.6 g of (R) 1-(3-phenoxyphenyl)-prop-2-yn-1-olwith a specific rotation of [α]_(D) ²⁰ =-16° (c=1% in benzene).

RMN Spectrum (deuterochloroform): peaks at 2.58-2.62 ppm (acetylenichydrogen); at 2.66 ppm (hydrogen of --OH); at 5.36-5.40 ppm (hydrogen oncarbon attached to ethynyl); at 6.83-7.50 (hydrogens of aromatic ring).

EXAMPLE 29 3-methyl-2-(S)-butanol

A mixture of 16.9 g of (1R, 5S)6,6-dimethyl-4(R)-[3-methyl-2(S)-butoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,70 ml of 2 N hydrochloric acid and 8.5 ml of acetone was heated at 50°C. with stirring for 16 hours and the mixture was cooled to 20° C. andextracted with ether. The combined ether extracts were washed with 2 Nammonium hydroxide solution, with water until the wash waters wereneutral, dried and evaporated to dryness under reduced pressure. Theoily product of 3-methyl-2(S)-butanol was distilled to obtain 1.7 g ofan oil with a boiling point of 108° C. at 760 mmHg and a specificrotation of [α]_(D) ²⁰ =+3°±1° (c=1.0% in ethanol).

RMN Spectrum (deuterochloroform): peaks at 1.08-1.2 ppm (hydrogens of1-methyl); at 1.5 ppm (hydrogen of OH); at 3.58 ppm (2-hydrogen); at1.58 ppm (3-hydrogen); at 0.85-0.95 ppm (hydrogens of 3- and 4-methyl).

EXAMPLE 30 3-methyl-2(R)-butanol

A mixture of 16 g of (1R, 5S)6,6-dimethyl-4(R)-[3'-methyl-2'(R)-butoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,70 ml of 2 N hydrochloric acid and 10 ml of acetone was stirred at 50°C. for 16 hours and was then cooled to 20° C. and extracted with ether.The combined ether extracts were washed with 2 N ammonium hydroxide andthen with water until the wash waters were neutral and dried andevaporated to dryness under reduced pressure. The 7 g of oil wasdistilled to obtain 1.5 g of 3-methyl-2(R)-butanol in the form of an oilwith a boiling point of 110° C. at 760 mm Hg and with a specificrotation of [α]_(D) ²⁰ =-4.5°±1° (c=1.3% in ethanol).

RMN Spectrum (deuterochloroform): peaks at 1.1-1.2 ppm (hydrogens of1-methyl); at 1.67 ppm (hydrogen of OH); at 3.58 ppm (2-hydrogen); at1.67 ppm (3-hydrogens); at 0.85-0.97 ppm (hydrogens of 3- and4-methyls).

EXAMPLE 31 2(S)-hydroxy-3,3-dimethyl-butyrolactone or (S)-pantolactone

A mixture of 20 g of (1R, 5S)6,6-dimethyl-4(R)-[3',3'-dimethylbutyrolactone-2'(S)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,100 ml of water, 100 ml of dioxane and 1 g of p-toluene sulfonic acidmonohydrate was refluxed with stirring for 2 hours and after cooling themixture to room temperature, 100 ml of water were added thereto. Themixture was concentrated under reduced pressure to about 50 ml and wasthen saturated with sodium chloride and was extracted with methylenechloride. The organic phase was dried and then evaporated to dryness at40° C. under reduced pressure to obtain a white product which was amixture of (S)-pantolactone and (1R, 5S)6,6-dimethyl-4(R)-hydroxy-3-oxabicyclo-(3,1,0)-hexan-2-one (product A).The latter was dissolved in 40 ml of refluxing water and the solutionwas cooled to room temperature. Crystallization was induced by additionof a few crystals of product A and the mixture was vacuum filtered. Thefilter was washed with water and the filtrate was evaporated to dryness.The residue was treated as before and was cooled to 0° to 5° C. for 2hours to recover more product A. The filtrate was then evaporated todryness and the residue was chromatographed over silica gel. Elutionwith a 6-4 toluene-ethyl acetate mixture yielded 7 g of white crystalscontaining product A. 6 g of the product were dissolved in 50 ml ofwater and 2 ml of ethanol and 25 ml of aqueous sodium bisulfite solutionwere added thereto. The mixture was energetically stirred at roomtemperature for 2 hours and was then saturated with sodium chloride andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness under reduced pressure at 40° C. to obtain 4.5 g of productwhich was sublimated at 90° C. at 0.1 mm Hg to obtain 2.7 g of(S)-pantolactone melting at ≃90° C. and having a specific rotation of[α]_(D) ²⁰ =+47.5°±1° (c=2% in water).

RMN Spectrum (deuterochloroform): peaks at 1.08-1.22 ppm (hydrogens ofgeminal methyls); at ˜3.77 ppm (hydrogen of --OH); at 3.98 ppm(hydrogens of 4-methylene of cyclopentyl); at 4.18 ppm (2-hydrogen ofcyclopentyl).

EXAMPLE 32 2(R)-hydroxy-3,3-dimethyl-butyrolactone or (R)-pantolactone

A mixture of 9 g of (1R, 5S)6,6-dimethyl-4(R)-[3',3'-dimethyl-butyrolactone-2'(R)-oxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,90 ml of methanol and 85 mg of p-toluene sulfonic acid monohydrate wasrefluxed with stirring for 2 hours and was then evaporated to drynessunder reduced pressure. The residue was chromatographed over silica geland was eluted with a 6-4 toluene-ethyl acetate mixture to obtain 1.3 gof yellow crystals which were sublimated at 90° C. at 0.1 mm Hg toobtain 1 g of (R)-pantolactone in the form of hydroscopic white crystalsmelting at 89° C. and having a specific rotation of [α]_(D) ²⁰ =-50°±1°(c=1.96% in water).

EXAMPLE 33 (3R, 3aR, 4S, 7R, 7aS) 3-[(1'R), (2'S),(5'R)-2'-isopropyl-5'-methylcyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one

A mixture of 1.66 g of (3R, 3aR, 4S, 7R, 7aS)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 2.34 g of menthol,50 mg of p-toluene sulfonic acid and 42 ml of benzene was refluxed withstirring for 90 minutes and was then cooled to room temperature andevaporated to dryness under reduced pressure. The 4.41 g of oil waschromatographed over silica gel and was eluted with a 95-5 benzene-ethylacetate mixture to obtain 2.76 g of (3R, 3aR, 4S, 7R, 7aS) 3-[(1'R),(2'S),(5'R)-2'-isopropyl-5'-methylcyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-onemelting at 54° C. and having a specific rotation of [α]_(D) ²⁰ =-120°±2°(c=1% in benzene) and 92 mg of isomer S melting at 100° C.

I.R. Spectrum (CHCl₃): absorption at 1769 cm⁻¹ (max.). and 1760 cm⁻¹(shoulder) (carbonyl of γ lactone); at 1390 cm⁻¹ (geminal methyls); at1117 cm⁻¹ (C--O--C).

RMN Spectrum (deuterochloroform): peaks at 068-0.8-0.92 ppm (hydrogensof methyls of isopropyl); at 0.88-0.97 ppm (hydrogens of methyl ofmenthol); at 2.67-3.67 ppm (1'-hydrogen of menthol and 3a-, 4-, 7 and 7ahydrogens of lactone); at 5.03-5.06 ppm (3-hydrogen of lactone); at 6.22ppm (ethylenic hydrogens).

Circular dichroism (dioxane): Δε=+2.3 at 217 nm (max.).

EXAMPLE 34 (3R, 3aR, 4S, 7R, 7aS) 3-[(1'R), (2'S), (5'R)2'-isopropyl-5'-methylcyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(product R) and (3R, 3aR, 4S, 7R, 7aS) 3-[(1'S), (2'R),(5'S)-2'-isopropyl-5'-methylcyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one(Product S)

A mixture of 6.65 g of (3R, 3aR, 4S, 7R, 7aS)3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one, 9.37 g of racemicmenthol, 200 mg of p-toluene sulfonic acid monohydrate and 170 ml ofbenzene was refluxed for 2 hours and was evaporated to dryness at 40° C.under reduced pressure to obtain 16.17 g of a brown oil. The latter waschromatographied over silica gel and was eluted with a 95-5benzene-ethyl acetate mixture and then a second time with a 98-2benzene-ethyl acetate mixture to obtain 3.58 g of product R in the formof a white product melting at 53° C. and a specific rotation of [α]_(D)²⁰ =-113.5°±3° (C=0.6 6% in benzene), 4.25 g of product S in the form ofa thick oil with a specific rotation of [α]_(D) ²⁰ =-74°±3° (c=0.3% inbenzene) and 0.57 g of a white wax which was a mixture of products R andS.

RMN Spectrum (deuterochloroform): Product R--peaks at 0.7-0.82-0.93 ppm(hydrogens of methyls of isopropyl); at 0.88-0.97 ppm (hydrogens ofmethyl); at 5.05-5.07 ppm (3-hydrogen of lactone); at 6.23 ppm(ethylenic hydrogens); at 2.67-3.67 ppm (1-hydrogen of menthol and 4-,3a-, 7 and 7a-hydrogens of lactone). Product S--peaks at 0.75-0.87-0.98ppm (hydrogens of methyls of isopropyl); at 0.92-0.87 ppm (hydrogens ofmethyl); at 4.92-4.95 ppm (3-hydrogen of lactone); at 6.23 ppm(ethylenic hydrogens).

EXAMPLE 35 (1R) (2S) (5R) 2-isopropyl-5-methyl-cyclohexanol

A mixture of 1.78 g of (3R, 3aR, 4S, 7R, 7aS) 3-[(1'R), (2'S), (5'R)2'-isopropyl-5'-methylcyclohexanoxy]-tetrahydro-4,7-methano-isobenzofuran-1-one,300 mg of p-toluene sulfonic acid monohydrate, 25 ml of water and 40 mlof dioxane was refluxed with stirring for one hour and 100 ml of waterwere added thereto. The dioxane was distilled at 40° C. under reducedpressure and the mixture was extracted with ether. The ether phase waswashed with water, dried and evaporated to dryness under reducedpressure to obtain 1.12 g of oil. The latter was chromatographed oversilica gel and was eluted with a 95-5 benzene-ethyl acetate mixture toobtain 750 mg of (1R) (2S) (5R) 2-isopropyl-5-methyl-cyclohexanolmelting at <50° C. and having a specific rotation of [α]_(D) ²⁰=-49°±2.5° (c=0.7% in ethanol).

I.R. Spectrum (CHCl₃): absorption at 1370 cm⁻¹ (geminal methyls); at3595 and 3610 cm⁻¹ (alcohol group).

EXAMPLE 36 (1R, 5S) 6,6-dimethyl-4(R)-[(1'R), (2'S), (5'R)2'-isopropyl-5'-methylcyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(product R) and (1R, 5S) 6,6-dimethyl-4(R)-[(1'S), (2'R), (5'S)2'-isopropyl-5'-methylcyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one(product S)

A mixture of 7.3 g of (1R, 5S)6,6-dimethyl-4(R)-hydroxy-3-oxabicyclo-(3,1,0)-hexa-2-one, 7,8 g ofracemic menthol, 100 mg of p-toluene sulfonic acid and 100 ml of benzenewas refluxed with stirring for 90 minutes and was then cooled to roomtemperature. 2 ml of triethylamine were added to the mixture toneutralize it and the mixture was evaporated to dryness under reducedpressure. The 15.7 g of colorless oil was chromatographed over silicagel and was eluted with a 98-2 methylene chloride-acetonitrile mixtureto obtain 5.74 g of product R melting at 83° C. and having a specificrotation of [α]_(D) ²⁰ =-180°±2.5° (c=1.1% in benzene) and 5.87 g ofproduct S in the form of an oil with a specific rotation of [α]_(D) ²⁰=-53°±2.5° (c=0.42% in benzene).

I.R. Spectrum (CHCl₃): Product R--absence of --OH and absorption at 1385cm⁻¹ (geminal methyls) and at 1795 (max.) and 1748 cm⁻¹ (shoulder) (C=0of γ-lactone). Product S--absence of OH and absorption at 1385 cm⁻¹(geminal methyls) and at 1795 (max.) and 1748 cm⁻¹ (C=0 of γ lactone).

RMN Spectrum (deuterochloroform): Product R--peaks at 2.0 ppm (1- and 5-hydrogens of lactone copule); at 1.15-1.18 ppm (hydrogens of methyls oflactone copule); at 5.35 ppm (4-hydrogen of lactone copule); at 3.58 ppm(1-hydrogen of menthol); at 0.82-0.99 ppm (hydrogens of 5-methyl ofmenthol; at 0.75-0.99 ppm (hydrogens of methyls of ispropyl). ProductS--peaks at 2.0 ppm (1- and 5- hydrogens of lactone copule); at1.17-1.18 ppm hydrogens of methyls of lactone copule); at 5.18 ppm(4-hydrogen of lactone copule); at 3.43 ppm (1-hydrogen or menthol); at0.75-0.98 ppm (hydrogens of 5-methyl of menthol); at 0.75-0.82 ppm(hydrogens of methyls and isopropyl).

Circular dichroism (dioxane): Product R--Δε=-3.65 at 224 nm (max.)Product S--Δε=-3.20 at 224-225 nm (max.)

EXAMPLE 37 (1R) (2S) (5R) 2-isopropyl-5-methyl-cyclohexanol

A mixture of 1 g of (1R, 5S) 6,6-dimethyl-4(R)-[(1'R), (2'S), (5'R)2'-isopropyl-5'-methyl-cyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,10 ml of water, 10 ml of dioxane and 100 mg of p-toluene sulfonic acidwas refluxed with stirring for 2 hours and the mixture was distilled toremove a maximum of dioxane. The mixture was diluted with water and wasextracted with isopropyl ether. The organic phase was dried andevaporated to dryness under reduced pressure to obtain 430 mg of oil.The latter was chromatographed over silica gel and was eluted with a 7-3cyclohexane-ethyl acetate mixture to obtain 350 mg of (1R), (2S), (5R)2-isopropyl-5-methyl-cyclohexanol identical to natural menthol. Theproduct melted at <50° C. and had a specific rotation of [α]_(D) ²⁰=-54.5°±1° (c=2% in ethanol).

EXAMPLE 38 (1S), (2R), (5S) 2-isopropyl-5-methyl-cyclohexanol

A mixture of 5 g of (1R, 5S) 6,6-dimethyl-4(R)-[(1'S) (2'R) (5'S)2'-isopropyl-5'-methylcyclohexanoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,25 ml of dioxane, 25 ml of water and 100 mg of p-toluene sulfonic acidwas refluxed with stirring for 2 hours and was distilled under reducedpressure to remove a maximum of dioxane. The mixture was diluted withwater and was extracted with isopropyl ether. The organic phase wasdried and evaporated to dryness under reduced pressure to obtain 4.8 gof an oil. The latter was chromatographed over silica gel to obtain 1.7g of (1S) (2R) (5S) 2-isopropyl-5-methyl-cyclohexanol melting at <50° C.and having a specific rotation of [α]_(D) ²⁰ =+46.5°±2.5° (c=0.35% inethanol).

Various modifications of the products and processes of the invention maybe made without departing from the spirit or scope thereof and it shouldbe understood that the invention is intended to be limited only asdefined in the appended claims.

We claim:
 1. An ether containing chiral atoms of the formula ##STR18##wherein chain A has the structure ##STR19## Y and Y' are individuallyselected from the group consisting of hydrogen, fluorine, bromine,chlorine and alkyl of 1 to 6 carbon atoms and Z is ##STR20##
 2. Acompound of claim 1 wherein chain A is a monocyclic hydrocarbon chain of3 to 6 carbon atoms.
 3. A compound of claim 1 wherein chain A has thestructure ##STR21##
 4. A compound of claim 1 selected from the groupconsisting of a mixture of (1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1R,5S)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,a mixture of (1S,5R) 6,6-dimethyl4-(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-oneand (1S,5R)6,6-dimethyl-4(R)-[1(R)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one,(1R,5S)6,6-dimethyl-4(R)-[1(S)-2-methyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-3-(3,1,0)-hexan-2-one,(1S, 5R)6,6-dimethyl-4-(R)-[1(R)-2-dimethyl-4-oxo-3-(2-propen-1-yl)-cyclopent-2-enyloxy]-3-oxabicyclo-(3,1,0)-hexan-2-one.